Depigmenting agents

ABSTRACT

The present invention is directed to 4-cyclopentyl resorcinol monohydrate, its Form I polymorph, formulations containing at least one of these compounds, and their use to lighten skin.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S.Provisional Patent Application Serial No. 60/446,665 filed Feb. 11,2003.

FIELD OF THE INVENTION

[0002] The present invention is directed to 4-cyclopentyl resorcinolmonohydrate and its Form I polymorph.

BACKGROUND OF THE INVENTION

[0003] In humans, skin color arises from a complex series of cellularprocesses that are carried out within a group of cells known asmelanocytes. Melanocytes are located in the lower part of the epidermisand their function is to synthesize a pigment, melanin, which protectsthe body from the damaging effects of ultraviolet radiation.

[0004] The mechanism by which skin pigmentation is formed,melanogenesis, involves the following main steps:Tyrosine→L-Dopa→Dopaquinone Dopachrome→Melanin. The first two reactionsin this series are catalyzed by the enzyme, tyrosinase. The activity oftyrosinase is promoted by the action of α-melanocyte stimulating hormoneand UV rays.

[0005] Typically, melanogenesis leads to a darker skin tone (i.e. atan). However, melanogenesis can lead to undesirable pigmentationpatterns as well. Examples of such undesirable pigmentation include agespots, liver spots, melasma, hyperpigmentation, etc. This has lead toresearch to find compounds that will inhibit melanogenesis. One of thetargets of this research is tyrosinase, the enzyme which catalyses theinitial steps in the generation of melanin.

[0006] U.S. Pat. No. 6,132,740 discloses a class of tyrosinaseinhibitors. These compounds are 4-cycloalkyl resorcinols. One compounddisclosed in the '740 patent is 4-cyclopentyl resorcinol. Example 2 ofthe '740 patent illustrates the preparation of 4-cyclopentyl resorcinol.The synthesis described in Example 2 can lead to the production of anoil. While this oil is a potent tyrosinase inhibitor, it may not bereadily produced in the quantities required to support clinicaldevelopment.

[0007] The synthesis of example 2 generates substantial quantities ofvarious positional isomers of 4-cyclopentyl resorcinol. Examples of suchisomers include 2-cyclopentyl resorcinol, 4,6-dicyclopentyl resorcinol,2,4-dicyclopentylresorcinol, etc. It is difficult to separate the4-cyclopentyl resorcinol from its positional isomers, especially whenall of the compounds are present as oils. Thus, a need exists in the artfor solid forms of 4-cyclopentyl resorcinol that may be produced morereadily than the anhydrate of the prior art.

SUMMARY OF THE INVENTION

[0008] In accordance with the present invention, a new solid form of4-cyclopentyl resorcinol has been discovered. The solid form is4-cyclopentyl resorcinol monohydrate. 4-Cyclopentyl resorcinolmonohydrate may be represented by the following formula:

[0009] A further aspect of the invention is directed to a specificcrystalline polymorph of 4-cyclopentyl resorcinol monohydrate. Thispolymorph is referred to as the Form I polymorph. It has acharacteristic powder X-ray diffraction pattern that is described infra(XRPD). The structure of a single crystal of the Form I polymorph hasalso been determined and is reported infra.

[0010] The monohydrate of 4-cyclopentyl resorcinol, and its Form Ipolymorph, may be used to lighten skin (i.e. as a depigmentation agent).In a more specific embodiment the compound is incorporated into atopical dosage form which the patient may apply directly to the area ofthe skin requiring lightening.

[0011] In a further embodiment, the invention is directed to an articleof manufacture containing either the monohydrate, or its Form Ipolymorph, packaged for retail distribution, in association withinstructions advising the consumer how to use the product to lightenskin.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 depicts the X-ray powder diffraction pattern for the Form Ipolymorph, on a scale of 2.5°2θ to 40°2θ.

[0013]FIG. 2 shows the X-ray powder diffraction pattern for the Form Ipolymorph depicted on a condensed scale of 7°2θ to 28°2θ.

[0014]FIG. 3 shows the X-ray powder diffraction from 4 different lots ofthe Form I polymorph.

DETAILED DESCRIPTION OF THE INVENTION A. Methods of Characterization

[0015] 1) Experimental X-Ray Powder Diffraction

[0016] Those X-ray powder diffraction (XPRD) analyses depicted in FIG. 3for lot numbers 2, 3, and 4 were carried out utilizing a ShimadzuXRD-6000 X-ray powder diffractometer using Cu K_(α) radiation. Theinstrument was equipped with a fine focus X-ray tube. The tube voltageand amperage were set to 40 kV and 40 mA, respectively. The divergenceand scattering slits were set at 1° and the receiving slit was set at0.15 mm. Diffracted radiation was detected by a NaI scintillationdetector. A theta-two theta continuous scan at 3°/min (0.4 sec/0.02°step) from 2.5 to 40°2θ was used. A silicon standard was analyzed tocheck the instrument alignment. Data were collected and analyzed usingShimadzu XRD-6000 v. 4.1 software. Samples were prepared for analysis byplacing them in a silicon sample holder and leveling with a frostedglass slide.

[0017] The X-ray powder diffraction (XPRD) analysis depicted in FIGS. 1,2, and FIG. 3, (lot #1), was carried out using a Inel XRG-3000diffractometer equipped with a curved position-sensitive detector, usingCu K_(α) Data was collected in real time over a two theta range of 120°at a resolution of 0.03°. The tube voltage and amperage were 40 kV and30 mA, respectively. The sample was packed in an aluminum holder with asilicon insert and analyzed. A silicon standard was analyzed each day tocheck for instrument alignment. Data were collected using INEL Winplotv. 3.11 software and analyzed using Shimadzu XRD-6000 v. 4.1 software.

[0018] As is readily apparent to one skilled in the art, the results ofany X-ray powder diffraction may vary. This variance can be due to testsample preparation, the particular model of X-ray diffractometer used,the operator's technique, etc. The term “approximately” if used indefining a position of a characteristic peak in an X-ray powderdiffraction pattern is defined as the stated 2θ value±0.2°2θ.

[0019] 2) X-ray Single Crystal Structure Determination

[0020] A single crystal of Form I was mounted in a random orientation.Preliminary examination and data collection were performed with Mo K_(α)radiation on a Bruker SAMRT IK CCD diffractometer, available from BrukerAXS, Inc., Madison, Wis. Cell constants and an orientation matrix fordata collection were obtained from least-squares refinement using thesetting angles of 6145 reflections in the range 3°<θ<28°. The structurewas solved by direct methods. The structure was refined by full-matrixleast-squares on F². The crystal structure was determined at 160 K,solved in space group P2₁/c and refined to a final R of 0.04 (F²>2σ).

B. 4-Cyclopentyl Resorcinol Monohydrate

[0021] As noted above, a new form of 4-cyclopentyl resorcinol has beendiscovered. This new form is the monohydrate of 4-cyclopentylresorcinol. This substance may be represented by the following formula:

[0022] The term “monohydrate” is typically used to describe a substancein which one molecule of water associates with one molecule of a givencompound (i.e. a 1:1 molar ratio). As used in this application, the term“monohydrate” should not be considered to have such a limited meaning.The inventors have discovered that the molar ratio of water to4-cyclopentyl resorcinol can vary. As used in this application, the term“4-cyclopentyl resorcinol monohydrate” refers to a substance whichcontains from about 0.7 moles of water to about 1.4 moles of water forevery mole of 4-cyclopentyl resorcinol. In a more specific embodiment,the monohydrate has about 0.8 to about 1.2 moles of water for every moleof 4-cyclopentyl resorcinol. In a more specific embodiment, themonohydrate has about 0.9 to about 1.2 moles of water for every mole of4-cyclopentyl resorcinol.

[0023] This new form posses a number of advantages over the form of theprior art. One of the primary advantages is the simplicity of separatingthe 4-cyclopentyl resorcinol from the positional isomers describedsupra, such as 2-cyclopentyl resorcinol, 4,6-dicyclopentyl resorcinol,2,4-dicyclopentylresorcinol. The reader's attention is directed toExamples 1-3 were this simplified recovery is demonstrated. The hydrateof 4-cyclopentyl resorcinol will crystallize from the reaction mixture.It may be separated from the positional isomers by filtration, ratherthan by distillation or column chromatography, as was required by theprior art form.

C. Form I Polymorph of 4-Cyclopentyl Resorcinol

[0024] 4-Cyclopentyl resorcinol monohydrate can exist as a crystallinepolymorph. One crystalline polymorph has been identified to date. Forsimplicity, it will be referred to as the “Form I polymorph”hereinafter.

[0025] The Form I polymorph can be identified by its characteristicX-ray powder diffraction pattern. A review of FIGS. I-III shows that theForm I polymorph exhibits three characteristic peaks. A characteristicpeak is one which has a

[0026] One occurs at approximately 8.1 degrees 2θ. A second occurs atapproximately 23.8 degrees 2θ. A third peak occurs at approximately 16.2degrees 2θ. Any one of these peaks alone, or in combination, may be usedto identify the Form I polymorph.

[0027] In addition to these characteristic peaks, a review of FIGS.I-III shows that other minor peaks have also been identified. Theintensity of these additional peaks vary with the particular orientationof the polymorph sample. These additional peaks may be used to confirmthe presence of the Form I polymorph, but there absence should not beused to determine that the particular material is not the Form Ipolymorph. These minor peaks include: 13.9, 14.3, 18.4, 19.3, 20.1,21.2, 25.8, and 26.54 (expressed in degrees 2θ,±0.2°2θ).

[0028] The structure of a single crystal of the Form I polymorph wasalso determined. The unit cell parameters are shown below in Table I.Table II depicts the atomic coordinates and isotropic displacementparameters. Table III depicts the hydrogen atom coordinates andisotropic displacement parameters. TABLE I Space Group and Unit CellParameters for Form I Polymorph Form I Crystal system monoclinic Spacegroup P2₁/c Cell Dimensions a(Å) 11.313 ± 0.001 b(Å)  7.495 ± 0.001 c(Å)12.881 ± 0.001 β(°) 110.00 ± 0.01 Volume(Å³)   987 ± 1 Z(Molecules/unitcell) 4 Density (g/cm³) 1.27 g/cm³ Temperature 160K

[0029] TABLE II Atomic Coordinates and Isotropic Displacement Parameters(Å²) for 4-Cyclopentyl Resorcinol Monohydrate Atom x y z U_(eq) C10.33884(11) 0.34881(15) 0.46048(9) 0.0200(3) C2 0.37848(11) 0.44298(16)0.55910(10) 0.0218(3) C3 0.34955(11) 0.62334(16) 0.55900(10) 0.0226(3)C4 0.28624(12) 0.70935(16) 0.46046(11) 0.0267(3) C5 0.24834(12)0.61175(17) 0.36262(10) 0.0251(3) C6 0.27024(11) 0.42885(16) 0.35932(9)0.0206(3) C7 0.22214(11) 0.31688(16) 0.25502(9) 0.0222(3) C8 0.15127(14)0.41590(19) 0.14728(10) 0.0323(3) C9 0.07751(14) 0.2711(2) 0.06620(11)0.0334(3) C10 0.07740(13) 0.10516(19) 0.13677(11) 0.0312(3) C110.12575(13) 0.17259(18) 0.25632(10) 0.0307(3) O1 0.36575(9) 0.16912(11)0.46057(7) 0.0265(2) O3 0.38290(10) 0.71979(12) 0.65606(8) 0.0301(2) O120.48669(10) 0.52361(12) 0.84256(7) 0.0265(2)

[0030] TABLE III Hydrogen Atom Coordinates and Isotropic DisplacementParameters (Å²) for 4-Cyclopentyl Resorcinol Monohydrate Atom x y zU_(eq) H2   0.4250 0.3848 0.6262 0.026 H4   0.2689 0.8335 0.4596 0.032H5   0.2058 0.6721 0.2953 0.030 H7   0.2960 0.2557 0.2450 0.027 H8A  0.2110 0.4772 0.1183 0.039 H8B   0.0932 0.5056 0.1597 0.039 H9A  0.1187 0.2441 0.0114 0.040 H9B −0.0096 0.3113 0.0263 0.040 H10A−0.0086 0.0557 0.1177 0.037 H10B   0.1335 0.0116 0.1255 0.037 H11A  0.1662 0.0752 0.3083 0.037 H11B   0.0565 0.2239 0.2774 0.037 H1  0.4093(16) 0.140(2) 0.5238(14) 0.032 H3   0.4151(16) 0.654(2)0.7117(14) 0.036 H12A   0.4323(15) 0.477(2) 0.8658(14) 0.032 H12B  0.5335(16) 0.440(2) 0.8378(13) 0.032

D. Method of Preparation

[0031]

[0032] 4Cyclopentyl resorcinol monohydrate, and its Form I polymorph,may be prepared by methods analogously known to those skilled in theart, which are depicted in Reaction Scheme I.

[0033] The initial step is the preparation of 4-cyclopentyl resorcinol.This may be accomplished as described in U.S. Pat. No. 6,132,740, whichis hereby incorporated by reference. A Friedel-Crafts reaction iscarried out in which resorcinol is contacted with an excess ofcyclopentanol, in the presence of a catalyst such as polyphosphoricacid, and the admixture is heated until the reaction is completed. The4-cyclopentyl resorcinol may be recovered by extraction. Evaporation ofthe organic phase of the extract generates an admixture of 4-cyclopentylresorcinol and its positional isomers.

[0034] In order to obtain the monohydrate of 4-cyclopentyl resorcinol,or its Form I polymorph, it is necessary to modify the isolation andrecovery procedures described above. This may be accomplished bysubjecting the anhydrate to a recrystallization, in the presence ofsufficient water, using techniques analogous to those known in the art.The anhydrate is dissolved in the recrystallization solvent, cooled, andthe desired monohydrate is allowed to precipitate from solution as theForm I polymorph. One suitable recrystallization solvent is an admixtureof water and toluene. The ratio of toluene to water can vary widely. TheForm I polymorph may be isolated by filtration, or evaporation, as isknown in the art.

[0035] It has been discovered that it is not necessary to carry outseparate extractions and recrystallizations. The Form I polymorph may berecovered directly by using an admixture of toluene and water as theextraction solvent. On cooling, the Form I polymorph crystallizes fromsolution. Likewise, other recrystallization solvents have also beenutilized. The Form I polymorph has been produced from admixtures ofethanol/water, methanol/water, and isopropanol/water. The reader'sattention is directed to Examples 1 to 3 where such recrystallizationsare described in greater detail.

E. Pharmacology and Dose

[0036] As noted above, U.S. Pat. No. 6,132,740 describes thepharmacology of 4-cyclopentyl resorcinol. It is a tyrosinase inhibitor.It may be used to inhibit the production of melanin by melanocytes (i.e.inhibition of melanogenesis). 4Cyclopentyl resorcinol monohydrate, andits Form I polymorph, are also tyrosinase inhibitors (hereinafter the“compounds”). They may be used in the same manner described in the '740patent to inhibit melanogenesis. Thus, the compounds may be used tolighten areas of the skin that are inappropriately pigmented.

[0037] Examples of such inappropriate pigmentation, include solar andsimple lentigines (including age/liver spots), melasma/chloasma andpostinflammatory hyperpigmentation. The compounds may also be used toreduce skin melanin content in non-pathological states so as to induce alighter skin tone, as desired by the user, or to prevent melaninaccumulation in skin, that has been exposed to UV irradiation. They canalso be used in combination with skin peeling agents (including glycolicacid or trichloroacetic acid face peels) to lighten skin tone andprevent repigmentation.

[0038] The compounds may also be used in combination with sun screens(UVA or UVB blockers) to prevent repigmentation, to protect against sunor UV-induced skin darkening or to enhance their ability to reduce skinmelanin and their skin bleaching action. The compounds used in thepresent invention can also be used in also be used in combination withascorbic acid, its derivatives and ascorbic-acid based products (such asmagnesium ascorbate) or other products with an anti-oxidant mechanism(such as resveratrol) which accelerate or enhance their ability toreduce skin melanin and their skin bleaching action.

[0039] As a general guideline the compounds will be administeredtopically. They will be applied directly to the areas of the skinrequiring depigmentation, or lightening. Topical formulations such as acreams, lotions, ointments, gels, etc. will be prepared which containfrom about 0.1 to 10 w/w % of the compounds. The compounds will then beapplied to the affected areas from 1 to 4 times daily. If the compoundsare administered systemically, then from about 0.1 mg/kg to about 100mg/kg will be administered daily, optionally as divided doses.

F. Pharmaceutical Formulations

[0040] If desired, the compounds can be administered directly withoutany carrier. However, to ease administration, they will typically beformulated into pharmaceutical carriers. Likewise, they will mosttypically be formulated into dermatological, or cosmetic carriers. Inthis application the terms “dermatological carrier” and “cosmetic”carrier are being used interchangeably. They refer to formulationsdesigned for administration directly to the skin or hair (i.e. topicalformulations).

[0041] For oral administration, the compounds can be formulated intosolid or liquid preparations such as capsules, pills, tablets, lozenges,melts, powders, suspensions, or emulsions. Solid unit dosage forms canbe capsules of the ordinary gelatin type containing, for example,surfactants, lubricants and inert fillers such as lactose, sucrose, andcornstarch or they can be sustained release preparations.

[0042] In another embodiment, the compounds can be tableted withconventional tablet bases such as lactose, sucrose, and cornstarch incombination with binders, such as acacia, cornstarch, or gelatin,disintegrating agents such as potato starch or alginic acid and alubricant such as stearic acid or magnesium stearate. Liquidpreparations are prepared by dissolving the active ingredient in anaqueous or non-aqueous pharmaceutically acceptable solvent, which mayalso contain suspending agents, sweetening agents, flavoring agents, andpreservative agents as are known in the art.

[0043] For parenteral administration the compounds may be dissolved in aphysiologically acceptable pharmaceutical carrier and administered aseither a solution or a suspension. Illustrative of suitablepharmaceutical carriers are water, saline, dextrose solutions, fructosesolutions, ethanol, or oils of animal, vegetative, or synthetic origin.The pharmaceutical carrier may also contain preservatives, buffers,etc., as are known in the art. When the compounds are being administeredintrathecally, they may also be dissolved in cerebrospinal fluid as isknown in the art.

[0044] Typically however, the compounds will be incorporated intoformulations suitable for topical administration. Any of the topicalformulations known in the art may be used. Examples of such topicalformulations include lotions, sprays, creams, ointments, salves, gels,etc. Actual methods for preparing topical formulations are known orapparent to those skilled in the art, and are described in detail inRemington's Pharmaceutical Sciences, 1990 (supra); and PharmaceuticalDosage Forms and Drug Delivery Systems, 6th ed, Williams & Wilkins(1995).

[0045] In a further embodiment, the formulations described above may bepackaged for retail distribution (i.e., a kit or article ofmanufacture). The package will contain instructions advising the patienthow to use the product in order to lighten their skin. Such instructionsmay be printed on the box, may be a separate leaflet or printed on theside of the container holding the formulation, etc.

G. EXAMPLES

[0046] The following examples are presented in order to furtherillustrate the invention. They should not be construed as limiting theinvention in any manner.

Example I

[0047] The following example describes one method for preparing4-cyclopentyl resorcinol monohydrate, as the Form I polymorph.

[0048] A round bottom flask equipped with stirrer bar was charged withresorcinol (150 g, 1.36 moles), cyclopentanol (125 ml, 1.38 moles) andphosphoric acid (85% in water) 500 ml. The flask was fitted with areflux condenser, purged with nitrogen and the mixture heated at 120° C.(oil bath temperature) for 26 h. After this time, TLC analysis indicatedthat starting resorcinol was still present. Further cyclopentanol (25ml, 0.28 moles) was added to the reaction mixture and heating continuedfor 2.5 hours. On cooling, the mixture was diluted with water (500 ml)and ethyl acetate (600 ml). The organic layer was separated, and theaqueous layer extracted with ethyl acetate (3×500 ml). The combinedorganic layers were neutralized by careful addition of an excess ofsaturated aqueous sodium hydrogen carbonate solution, washed with brine(300 ml), dried (magnesium sulfate) and concentrated. The residue wasdissolved in toluene (500 ml) and water (20 ml, 1.11 moles, 0.8 eq)added. The solution was stirred for ca 30 s and cooled in an ice/waterbatch with periodic stirring. After 4 h the solid was filtered and leftto air dry in a crystallizing dish for 16 h to give the Form I polymorphas colored crystals (118.22 g. Recrystallization in toluene afforded theForm I polymorph as white plates (93 g, 35%). Found C, 67.44, H 8.22%;C₁₁H₁₆O₃ requires C 67.32, H 8.22%. IR Data (ν_(max)/cm⁻¹): 3199.2 br,2963.8 s, 2863.5 s, 1624.2 m, 1604.7 s, 1528.3 s, 1457.3 s, 1395.3 s,1349.7 w, 1287.4 m, 1265.2 s, 1228.0 s, 1179.4 m, 1166.9 m, 1108.1 s,977.8 s, 826.5 s, 749.1 m, 723.9 m, 703.8 m and 627.9 m.

[0049] A X-ray powder diffraction pattern was generated with a sample of4-cyclopentyl resorcinol monohydrate produced as described above. Theresults of this testing are depicted in FIGS. I, II and FIG. III (Lot#1).

Example II

[0050] A single crystal of the Form I polymorph was obtained byrecrystallization from isopropanol and water. The structure of thissingle crystal of the Form I polymorph is reported in Table I above.

Example III

[0051] The protocol below describes an alternative method for preparing4-cyclopentyl resorcinol monohydrate. Toluene and water are used as theextracting solvent.

[0052] To a N₂ purged pressure reactor is charged resorcinol (44.0 g.0.40 mol), cyclopentanol (44 mL, 0.49 mol) and 85% aqueous H₃PO₄ (55 mL.0.80 mol). The slurry is heated to 95-120° C. for 6-18 hours. The pinkreaction mixture is cooled to −70° C. and diluted with water (50 mL) andtoluene (200 mL). The layers are allowed to separate at 60±5° C. Thebottom orange aqueous layer is cut away. The remaining pink organiclayer is extracted with 2×50 mL water at 60±5° C. and then stirred withcarbon (5 g) at 60±5° C. for 1-2 hours. The slurry is filtered hotthrough Supercel, rinsing the cake with hot toluene (50 mL). The orangefiltrate is diluted with 5 mL water and allowed to cool to −30° C. atwhich time the product crystallizes. The slurry is cooled to 0-5° C. andthe product collected, washed with cold toluene (40 mL) and pulled dryon the funnel to afford 41 g of 4-cyclopentyl resorcinol monohydrate asa white to pale pink solid (≧98% area by HPLC). The material can berecrystallized if desired from hot toluene (5 mL/g) and carbon (10% byweight) filtering through Supercel and/or silica gel to the Form Ipolymorph of 4-cyclopentyl resorcinol afford as a white solid (≧99.7% byHPLC).

[0053] The powdered X-ray diffraction pattern was determined for three(3) different lots of the Form I polymorph produced by the protocoldescribed above. FIG. III depicts this data (Lot #'s 2-4).

Example IV

[0054] The water content of 4-cyclopentyl resorcinol monohydrate,produced as in Example 1, was determined by Karl Fischer analysis. Theseanalysis were conducted in the following manner:

[0055] i) Coulometric Karl Fischer (KF) Analysis

[0056] The analysis was performed using a Mettler Toledo DL39 KarlFischer titrator. Approximately 15-20 mg of sample was placed in the KFtitration vessel containing Hydranal—Coulomat AD and mixed for 10seconds to ensure dissolution. The sample was then titrated by means ofa generator electrode which produces iodine by electrochemicaloxidation: 2 I−=>I₂+2e. Three replicates were obtained to ensurereproducibility.

[0057] ii) Volumetric Karl Fischer (KF) analysis for water determination

[0058] The analysis was performed using a Mettler Toledo DL38 KarlFischer titrator. Approximately 10-20 mg of sample was placed in the KFtitration vessel containing Hydranal methanol-dry and mixed for 10seconds to ensure dissolution. The sample was then titrated withHydranal Composite 5 to an appropriate endpoint. Two replicates wereobtained to ensure reproducibility. The titrant was standardized withHydranal Water Standard 10.0.

[0059] The following results were obtained: TABLE II Average Run 1 Run 2Run 3 Average No. mols. Method % H₂O % H₂O % H₂O % H₂O H₂O Volumetric8.95 9.04 — 9.00 1.08 Volumetric 9.22 9.80 — 9.51 1.15 Coulometric 8.128.21 8.58 8.30 0.99

[0060] The data in Table II demonstrates that Applicants have producedthe monohydrate of 4-cyclopentyl resorcinol.

What is claimed is:
 1. 4-Cyclopentyl resorcinol monohydrate.
 2. Form Ipolymorph of 4-cyclopentyl resorcinol monohydrate.
 3. A crystallinepolymorph of 4-cyclopentyl resorcinol monohydrate that exhibits an X-raypowder diffraction pattern having a characteristic peak expressed indegrees 2θ at approximately 8.1.
 4. A crystalline polymorph of4-cyclopentyl resorcinol monohydrate that exhibits an X-ray powderdiffraction pattern having a characteristic peak expressed in degrees 2θat approximately 23.8.
 5. A crystalline polymorph of 4-cyclopentylresorcinol monohydrate that exhibits an X-ray powder diffraction patternhaving characteristic peaks expressed in degrees 2θ at approximately 8.1and 23.8.
 6. The crystalline polymorph according to claim 5 thatexhibits a characteristic peak expressed in degrees 2θ at approximately16.2.
 7. The crystalline polymorph according to claim 5 which exhibitsat least one peak expressed in degrees 2θ at approximately 20.0 and25.8.
 8. The crystalline polymorph according to claim 5 which exhibitsat least one peak expressed in degrees 2θ at approximately 13.9, 14.3,18.4, 19.3, 20.0, 21.3, 25.8 or 26.5.
 9. The crystalline polymorph ofclaim 2, which exhibits an X-ray powder diffraction patternsubstantially similar to that depicted in FIG. I.
 10. The crystallinepolymorph of claim 2 which exhibits an X-ray powder diffraction patternsubstantially similar to that depicted for Lot #'s 2, 3, or 4 in FIG.III.
 11. A crystalline polymorph of 4-cyclopentyl resorcinol monohydratethat exhibits a single crystal X-ray crystallographic analysis at 160 Kwith crystal unit cell parameters that are equal to the following: TABLEI Space Group and Unit Cell Parameters for Form I Polymorph Form ICrystal system monoclinic Space group P2₁/c Cell Dimensions a(Å) 11.313± 0.001 b(Å)  7.495 ± 0.001 c(Å) 12.881 ± 0.001 β(°) 110.00 ± 0.01Volume(Å³)   987 ± 1 Z(Molecules/unit cell) 4 Density (g/cm³) 1.27 g/cm³Temperature 160K


12. A method for lightening skin comprising administering a compoundaccording to claim 1 to a patient in need thereof.
 13. A method forreducing pigmentation in skin comprising administering a compoundaccording to claim 1 to a patient in need thereof.
 14. A pharmaceuticalformulation comprising an effective amount of a compound according toclaim 1 in admixture with at least one pharmaceutically acceptablecarrier.
 15. A process for producing 4-cyclopentyl resorcinolmonohydrate comprising contacting 4-cyclopentyl resorcinol with anadmixture of a suitable recrystallization solvent and water underconditions suitable to initiate the precipitation of said 4-cyclopentylresorcinol monohydrate from the admixture and optionally collecting said4-cyclopentyl resorcinol monohydrate.